3-Phosphoinositide-dependent protein kinase-1 (PDK1) is a 556-amino acid containing enzyme comprised of a C-terminal Pleckstrin homology (PH) domain (residues 459-550) and an N-terminal kinase domain (residues 70-359). The PH domain of PDK1 binds phosphatidylinositols (e.g., phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-triphosphate) produced by phosphatidylinositol kinases, such as phosphatidylinositol 3-kinase (PI3K) and whose levels are, in part, controlled by phosphatases such as PTEN (phosphatase and tensin homologue). PDK1 plays a central role in the PI3K/Akt pathway and has been called a “master regulator” kinase due to its role as a critical upstream activating kinase that phosphorylates the so-called T-loop phosphorylation site for multiple kinases in the AGC family of kinases including but not limited to all three isoforms of PKB (PKBα, PKBβ, PKBγ, also known as Akt1, Akt2, and Akt3, respectively), RSK (three isoforms RSK1, RSK2, RSK3, also known as p90RSK), p70S6K (two isoforms, S6K1 and S6K2), SGK1 and PKC.
Signals from several peptide growth factors including insulin, insulin-like growth factor-1 and platelet-derived growth factor are transduced by PKB. Like PDK1, PKB contains a PH domain that binds phosphatidyl 3,4,5-triphosphate. PKB is translocated to the plasma membrane and phosphorylated by PDK1 at residue T-308/309 (the two phosphosites correspond to different isoforms) in response to the second messenger phosphatidyl 3,4,5-triphosphate produced by PI3K. Activation of PKB in tumor cells results in increased cellular survival via anti-apoptotic signals and also proliferation. PKBβ amplification has been observed in a proportion of several tumor types including ovarian, breast and pancreatic cancers. Similarly, PKBα amplification has been observed in a percentage of gastric adenocarcinoma samples. Recently, an activated mutant form of PKBα (E17K) was detected in a number of breast (8%), colorectal (6%), and ovarian (2%) cancers. PDK1 kinase inhibitors are useful as treatments for diseases linked to PKB signaling (such as cancer, Cowden syndrome, Lhermitte-Dudos disease and Bannayan-Zonana syndrome) by preventing activation of PKB signaling by PDK1.
Similarly, PDK1 kinase inhibitors are useful for treating cancer or other proliferative disorders by blocking the activation of p70S6K by PDK1. There are several substrates of p70S6K, such as ribosomal S6 protein, eIF4B, PDCD4 etc., that are involved in translation inhibition complex formation or ribosomal protein synthesis. Inhibition of protein synthesis via inhibition of phosphorylation of ribosomal S6 protein is believed to inhibit the proliferation of tumor cells by mTOR inhibitors (e.g., rapamycin). p70S6K gene amplification has been observed in breast tumor specimens. Simultaneous amplification of p70S6K and HER-2 correlates with poor survival in cancer patients. Hyperactivation of p70S6K (as measured by phosphorylation of T389) has been observed by immunohistochemical analysis of breast, head and neck squamous cell carcinoma (HNSCC), glioblastoma, lung and liver primary tumor specimens.
Likewise, PDK1 kinase inhibitors are useful for the treatment of cancer by blocking the activation of RSK1 (also known as p90RSK) by PDK1. RSK1 transduces anti-apoptotic and proliferative signals be mediating phosphorylation directly or indirectly of BAD, LKB1, TSC2, NFkB, mTOR. Ras/MAPK pathway is activated in >50% in primary tumors. RSK1 activity is correlated with MAPK activity. RSK1 is overexpressed in primary breast and prostate cancer samples.
PDK1 signaling regulates multiple critical steps in angiogenesis. Inhibitors of the activity of PDK1 are thus useful in the treatment of cancer, in particular cancers associated with deregulated activity of the PTEN/PI3K pathway including, but not limited to PTEN loss of function mutations, PI3K gain of function mutations and receptor tyrosine kinase gain of function mutations.
PDK1 signaling has also been implicated in tumorigenesis and a PDK1 inhibitor is useful for tumor prevention or prevention of tumor recurrence. Mice with a PTEN heterozygous (PTEN+/−) genotype are well-known to spontaneously develop tumors. Alessi and co-workers found that PDK1 hypomorphic PTEN+/− mice expressing <30% of normal PDK1 protein levels showed a significant delay in tumor formation as compared to littermate controls expressing normal levels of PDK1 protein (Current Biology, 2005, 15, 1839-1846).
SGK1 (serum and glucocorticoid-regulated kinase-1) activity is critical for insulin-mediated Na+ retention and hypertensive effects. Inhibition of SGK1 activity by a PDK1 kinase inhibitor is useful in treating hypertension and/or hypoinsulinemia.
It is an object of the instant invention to provide novel compounds that are inhibitors of PDK1.
It is also an object of the present invention to provide pharmaceutical compositions that comprise the novel compounds that are inhibitors of PDK1.
It is also an object of the present invention to provide a method for treating cancer that comprises administering such inhibitors of PDK1 activity.
It is also an object of the present invention to provide a method for treating tumor recurrence that comprises administering such inhibitors of PDK1 activity.
It is also an object of the present invention to provide a method for treating hypertension that comprises administering such inhibitors of PDK1 activity.
It is also an object of the present invention to provide a method for treating diabetes mellitus that comprises administering such inhibitors of PDK1 activity.